Publications by authors named "Erin S Murphy"

56 Publications

Outcomes of salvage radiation for recurrent world health organization grade II meningiomas: a retrospective cohort study.

J Neurooncol 2021 Feb 15. Epub 2021 Feb 15.

Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.

Purpose: The optimal modality of radiation-intensity-modulated radiation therapy (IMRT) or stereotactic radiosurgery (SRS)-in patients with recurrent WHO grade II meningiomas is not well-established. The purpose of this study was to compare progression-free survival (PFS) in patients undergoing salvage IMRT vs SRS. We compared PFS in those with and without history of prior radiation.

Methods: Forty-two patients with 71 tumor recurrences treated with IMRT or SRS were retrospectively reviewed. Thirty-two salvage treatments were performed on recurrent tumors never treated with prior radiation ('radiation-naïve' cohort), whereas 39 salvage treatments were performed on recurrent tumors previously treated with radiation ('re-treatment cohort').

Results: In the 'radiation-naïve' cohort, 3-year PFS for IMRT and SRS was 68.8% and 60.7%, respectively (p = 0.61). The median tumor volume for patients treated with IMRT was significantly larger than for patients treated with SRS (5.7 vs 2.2 cm; p = 0.04). The 3-year PFS for salvage IMRT or SRS in the 're-treatment' cohort was 45.4% vs 65.8% in the 'radiation-naïve' cohort (p = 0.008). When analyzing the outcome of multiple re-treatments, median PFS was 47 months for 1 or 2nd salvage radiation (IMRT or SRS) compared to 16 months for the 3rd or greater salvage radiation treatment (p = 0.003).

Conclusion: For salvage radiation of recurrent grade II tumors that are 'radiation-naïve', comparable 3-year PFS rates were found between IMRT and SRS, despite the IMRT group having significantly larger tumors. Salvage radiation overall was less successful in the 're-treatment' cohort compared with the 'radiation-naïve' cohort. Additionally, the effectiveness of radiation significantly declines with successive salvage radiation treatments.
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http://dx.doi.org/10.1007/s11060-021-03711-zDOI Listing
February 2021

Multiple Site SBRT in Pediatric, Adolescent, and Young Adult Patients With Recurrent and/or Metastatic Sarcoma.

Am J Clin Oncol 2021 Mar;44(3):126-130

Department of Radiation Oncology.

Background: Stereotactic body radiation therapy (SBRT) is increasingly used for patients with recurrent and or metastatic tumors. Sarcomas are generally considered not sensitive to radiotherapy and SBRT may allow for increased biological effectiveness. We report intermediate outcomes and toxicity for pediatric, adolescent, and young adult patients treated with SBRT to sites of recurrent and or metastatic sarcoma.

Procedure: We queried an Institutional Review Board-approved registry of patients treated with SBRT for metastases from pediatric sarcomas. Patients age 29 and below were assessed for local control, survival, and toxicity.

Results: Thirty-one patients with a total of 88 lesions met eligibility criteria. Median patient age was 17.9 years at treatment. Sixteen patients were treated with SBRT to >1 site of disease. The median dose was 30 Gy in 5 fractions. The median follow-up time was 7.4 months (range: 0.2 to 31.4 mo). Patients were heavily pretreated with systemic therapy. In 57 lesions with >3 months of radiographic follow-up, the 6-month and 12-month local control rates were 88.3%±4.5% and 83.4%±5.5%, respectively. Radiographic local failures were rare (6/57 in-field, 4/57 marginal). Only 1/88 treated lesions was associated with a radiation-related high-grade toxicity; late grade 3 intestinal obstruction in a re-irradiated field while on concurrent therapy (gemcitabine and docetaxel). No acute grade ≥3 toxicity was observed.

Conclusions: SBRT was well tolerated in the majority of patients with favorable local control outcomes. Additional studies will be required to determine the optimal SBRT dose and fractionation, treatment volume, and appropriate concurrent therapies.
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http://dx.doi.org/10.1097/COC.0000000000000794DOI Listing
March 2021

Treatment paradigms for oligometastatic pediatric cancers: a narrative review with a focus on radiotherapy approaches.

Ann Palliat Med 2020 Oct 27. Epub 2020 Oct 27.

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

There is a growing body of prospective evidence describing an oligometastatic phenotype in adults for whom local metastasis-directed therapy can improve outcomes in select patients. However, a relative paucity of data for pediatric patients with oligometastatic disease creates challenges in choosing optimal treatment. The purpose of this review is to evaluate the literature surrounding pediatric oligometastatic disease and treatment, specifically focusing on the role of radiotherapy. A review of studies ranging from 2008 to 2020 was performed. The radiotherapy techniques evaluated included conventionally fractionated radiotherapy, stereotactic body radiotherapy (SBRT), and stereotactic radiosurgery (SRS). Our search yielded 6 studies evaluating conventionally fractionated radiotherapy, 9 studies of SBRT, and 3 studies of spine SRS. Metastasis-directed therapy for treatment of pediatric oligometastasis is generally well-tolerated, is associated with favorable local control, and is shown to improve event-free survival and progression-free survival (PFS) outcomes in select pediatric patients. Pediatric patients with oligometastatic disease may benefit from aggressive local therapy to metastatic sites in conjunction with a comprehensive treatment paradigm. Retrospective data have led to promising prospective trials that will further clarify patient selection and management. Additional data are needed to elucidate long term oncologic and toxicity outcomes.
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http://dx.doi.org/10.21037/apm-20-1023DOI Listing
October 2020

Aggressive Local Control With Multisite Stereotactic Body Radiation in Metastatic Ewing Sarcoma: A Literature Review and Case Report.

Anticancer Res 2020 Feb;40(2):951-955

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, U.S.A.

Ewing sarcoma (ES) is an undifferentiated small round blue cell tumor most commonly originating in the bone of adolescents 10-20 years of age, although 30% are diagnosed in adults. The most important prognostic factor is the presence of metastatic disease. Results of the EURO-EWING 99 trial of ES patients showed that local treatment of not only the primary, but also of the sites of metastatic disease should be considered to improve event-free survival. The use of stereotactic body radiotherapy (SBRT) has been extensively reported for tumors of lung, liver, pancreas, and spine. The use of SBRT in these sites is well-accepted. Here, we report a detailed case of SBRT to multisite metastatic ES. We demonstrate the feasibility, safety, and efficacy of aggressive local control with multisite SBRT for the treatment of metastatic ES.
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http://dx.doi.org/10.21873/anticanres.14028DOI Listing
February 2020

Outcomes of stereotactic radiosurgery for pilocytic astrocytoma: an international multiinstitutional study.

J Neurosurg 2019 Nov 29:1-9. Epub 2019 Nov 29.

13Rose-Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland, Ohio.

Objective: The current standard initial therapy for pilocytic astrocytoma is maximal safe resection. Radiation therapy is considered for residual, recurrent, or unresectable pilocytic astrocytomas. However, the optimal radiation strategy has not yet been established. Here, the authors describe the outcomes of stereotactic radiosurgery (SRS) for pilocytic astrocytoma in a large multiinstitutional cohort.

Methods: An institutional review board-approved multiinstitutional database of patients treated with Gamma Knife radiosurgery (GKRS) between 1990 and 2016 was queried. Data were gathered from 9 participating International Radiosurgery Research Foundation (IRRF) centers. Patients with a histological diagnosis of pilocytic astrocytoma treated using a single session of GKRS and with at least 6 months of follow-up were included in the analysis.

Results: A total of 141 patients were analyzed in the study. The median patient age was 14 years (range 2-84 years) at the time of GKRS. The median follow-up was 67.3 months. Thirty-nine percent of patients underwent SRS as the initial therapy, whereas 61% underwent SRS as salvage treatment. The median tumor volume was 3.45 cm3. The tumor location was the brainstem in 30% of cases, with a nonbrainstem location in the remainder. Five- and 10-year overall survival rates at the last follow-up were 95.7% and 92.5%, respectively. Five- and 10-year progression-free survival (PFS) rates were 74.0% and 69.7%, respectively. On univariate analysis, an age < 18 years, tumor volumes < 4.5 cm3, and no prior radiotherapy or chemotherapy were identified as positive prognostic factors for improved PFS. On multivariate analysis, only prior radiotherapy was significant for worse PFS.

Conclusions: This represents the largest study of single-session GKRS for pilocytic astrocytoma to date. Favorable long-term PFS and overall survival were observed with GKRS. Further prospective studies should be performed to evaluate appropriate radiosurgery dosing, timing, and sequencing of treatment along with their impact on toxicity and the quality of life of patients with pilocytic astrocytoma.
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http://dx.doi.org/10.3171/2019.9.JNS191335DOI Listing
November 2019

Spine radiosurgery in adolescents and young adults: early outcomes and toxicity in patients with metastatic Ewing sarcoma and osteosarcoma.

J Neurosurg Spine 2019 Nov 29:1-8. Epub 2019 Nov 29.

1Department of Radiation Oncology, Taussig Cancer Institute.

Objective: There are limited data on spine stereotactic radiosurgery (SRS) in treating adolescent and young adult (AYA) patients. SRS has the advantages of highly conformal radiation dose delivery in the upfront and retreatment settings, means for dose intensification, and administration over a limited number of sessions leading to a decreased treatment burden. In this study, the authors report the oncological and toxicity outcomes for AYA patients with metastatic sarcoma treated with spine radiosurgery and provide clinicians a guide for considerations in dose, volume, and fractionation.

Methods: An institutional review board-approved database of patients treated with SRS in the period from October 2014 through December 2018 was queried. AYA patients, defined by ages 15-29 years, who had been treated with SRS for spine metastases from Ewing sarcoma or osteosarcoma were included in this analysis. Patients with follow-ups shorter than 6 months after SRS were excluded. Local control, overall survival, and toxicity were reported.

Results: Seven patients with a total of 11 treated lesions were included in this study. Median patient age was 20.3 years (range 15.1-26.1 years). Three patients had Ewing sarcoma (6 lesions) and 4 patients had osteosarcoma (5 lesions). The median dose delivered was 35 Gy in 5 fractions (range 16-40 Gy, 1-5 fractions). The median follow-up was 11.1 months (range 6.8-26.0 months). Three local failures were observed within the follow-up period. No acute grade 3 or greater toxicity was observed. One patient developed late grade 3 toxicity consisting of radiation enteritis. This patient had previously received radiation to an overlapping volume with conventional fractionation. SRS re-irradiation for this patient was also performed concurrently with chemotherapy administration. No late grade 4 or higher toxicities were observed. No pain flare or vertebral compression fracture was observed. Three patients died within the follow-up period.

Conclusions: SRS for spine metastases from Ewing sarcoma and osteosarcoma can be considered as a treatment option in AYA patients and is associated with acceptable toxicity rates. Further studies must be conducted to determine long-term local control and toxicity for this treatment modality.
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http://dx.doi.org/10.3171/2019.9.SPINE19377DOI Listing
November 2019

Malignant Transformation of Molecularly Classified Adult Low-Grade Glioma.

Int J Radiat Oncol Biol Phys 2019 12 25;105(5):1106-1112. Epub 2019 Aug 25.

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.

Purpose: Malignant transformation (MT) of adult grade 2 glioma (low-grade glioma [LGG]) is associated with adverse survival. We sought to describe the incidence, outcomes, and risk factors for MT of molecularly classified LGG.

Methods And Materials: We reviewed a single-institutional database of adults who received a diagnosis of LGG with data allowing for molecular classification from 1980 to 2018 to evaluate time to MT and its associated risk factors. MT was defined as pathologic confirmation of grade 3-4 glioma and/or imaging characteristics consistent with MT by multidisciplinary consensus.

Results: Among the included 486 adults with molecularly classified LGG, median age was 39 years (range, 18-78), median tumor size was 3.9 cm (range, 0.3-13.0), and 262 (54%) were male. Molecular classification was IDH1p/19q in 169 (35%), IDH1p/19q in 125 (26%), and IDH in 192 (40%) patients. Adjuvant management was observation in 246 (51%) patients, temozolomide alone in 82 (16%), radiation therapy alone in 63 (13%), and radiation therapy concurrent with temozolomide in 81 (17%). Temozolomide monotherapy was more likely to be given to IDH1p/19q patients (P < .001). Median follow-up was 5.3 years. MT occurred in 84 (17%) patients, with a 5-year freedom from MT of 86% (95% confidence interval [CI], 82%-90%). Median overall survival after MT was 2.4 years (95% CI, 1.5-3.3) and was associated with molecular classification (P = .03) and grade at MT (P < .001). Factors associated with MT were male sex (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6; P = .009), tumor size ≥5 cm (HR, 3.5; 95% CI, 2.0-6.2; P < .001), IDH1p/19q (HR, 2.7; 95% CI, 1.3-5.6; P = .009) or IDH classification (HR, 5.5; 95% CI, 2.5-11.8; P < .001), and adjuvant temozolomide monotherapy (HR, 3.8; 95% CI, 1.4-10.3; P = .008).

Conclusions: MT of LGG has a poor prognosis associated with unfavorable molecular groups. Analysis of our large cohort identified adjuvant temozolomide monotherapy as the only modifiable risk factor for MT and provides the first clinical evidence of temozolomide-associated MT among molecularly classified adult LGG. This novel finding supplements our understanding of temozolomide-induced hypermutation and informs precision management of LGG.
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http://dx.doi.org/10.1016/j.ijrobp.2019.08.025DOI Listing
December 2019

Mentors' perspectives on the successes and challenges of mentoring in the COG Young Investigator mentorship program: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2019 10 16;66(10):e27920. Epub 2019 Jul 16.

Division of Pediatric Hematology-Oncology, Children's Hospital of Los Angeles, Los Angeles, California.

Background: Identification and development of young investigators (YI) is critical to the long-term success of research organizations. In 2004, the Children's Oncology Group (COG) created a mentorship program to foster the career development of YIs (faculty <10 years from initial appointment). This study sought to assess mentors' long-term assessment of this program.

Procedure: In 2018, 101 past or current mentors in the COG YI mentorship program completed an online survey. Statistical comparisons were made with the Kruskal-Walis test.

Results: The response rate was 74.2%. As some mentors had multiple mentees, we report on 138 total mentee-mentor pairs. Mentors were 57.4% male, and mentees were 39.1% male. Mentors rated being mentored as a YI as important with a median rating of 90 on a scale of 1-100, interquartile range (IQR) 80-100. Most mentors reported that being mentored themselves helped their own success within COG (78.2%) and with their overall career development (92.1%). Most mentors enjoyed serving in the program (72.3%) and the median success rating (on a scale of 1-100) across the mentor-mentee pairings was 75, IQR 39-90. Success ratings did not differ by mentor/mentee gender, but improved with increased frequency of mentor-mentee interactions (P < .001). Mentor-mentee pairs who set initial goals reported higher success ratings than those who did not (P < .001). Tangible successes included current mentee COG committee involvement (45.7%), ongoing mentor-mentee collaboration (53.6%), and co-authored manuscript publication (38.4%).

Conclusion: These data indicate that mentorship is important for successful professional development. Long-term mentoring success improves when mentors and mentees set goals upfront and meet frequently.
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http://dx.doi.org/10.1002/pbc.27920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707882PMC
October 2019

Risk Factors for Progression Among Low-Grade Gliomas After Gross Total Resection and Initial Observation in the Molecular Era.

Int J Radiat Oncol Biol Phys 2019 08 22;104(5):1099-1105. Epub 2019 Apr 22.

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Purpose: To identify risk factors for progression-free survival (PFS) in the molecular era among patients with low-grade glioma (LGG) who undergo gross total resection (GTR) followed by initial observation.

Methods And Materials: We reviewed patients with World Health Organization grade 2 LGG treated at a single institution. We included only those who underwent magnetic resonance imaging (MRI)-confirmed GTR followed by initial observation. Molecular classification was obtained at either the time of diagnosis or pathology review. Cox proportional hazards regression, the Kaplan-Meier method, and the log-rank test were used. P values <.05 were considered statistically significant.

Results: We included 144 patients who underwent MRI-confirmed GTR between 1994 and 2014 followed by initial observation. Median age was 29 years (interquartile range [IQR], 18-41), median tumor size was 2.7 cm (IQR, 1.8-4.0), and median follow-up was 81 months (IQR, 36-132). Molecular classification was 13% IDH-mutant 1p19q-codeleted; 21% IDH-mutant 1p19q-intact; 39% IDH1-R132H-wildtype; and 28% undetermined. For the entire cohort, 5- and 10-year PFS and overall survival were 71% and 53%, and 98% and 90%, respectively. On multivariate analysis, factors associated with worse PFS included increasing age at diagnosis (hazard ratio [HR], 1.05; 95% CI, 1.00-1.09; P = .03), increasing preoperative tumor size (HR, 1.07; 95% CI, 1.04-1.10; P < .0001), and IDH-mutant 1p19q-intact classification (HR, 3.18; 95% CI, 1.15-8.74, P = .025). Median PFS for patients with IDH-mutant 1p19q-codeleted, IDH-mutant 1p19q-intact, and IDH1-R132H-wildtype tumors were 113 months, 56 months, and not reached, respectively. Molecular classification was significantly associated with PFS (P < .0001) but not overall survival (P = .20).

Conclusions: Among patients with LGG who undergo MRI-confirmed GTR and initial observation in the molecular era, increasing age, increasing tumor size, and IDH-mutant 1p19q-intact classification are associated with worse PFS. Because tumor progression is associated with adverse health-related quality of life, these factors may aid clinicians and patients in the shared decision-making process regarding goals of surgery and timing of postoperative therapy. Further study is required to elucidate why IDH-mutant 1p19q-intact LGGs are at higher risk for early progression.
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http://dx.doi.org/10.1016/j.ijrobp.2019.04.010DOI Listing
August 2019

The impact of sequencing PD-1/PD-L1 inhibitors and stereotactic radiosurgery for patients with brain metastasis.

Neuro Oncol 2019 08;21(8):1060-1068

Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland, Ohio.

Background: The response of brain metastases (BM) treated with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs; programmed cell death 1 and its ligand) is of significant interest.

Methods: Patients were divided into cohorts based on ICI sequencing around SRS. The primary outcome was best objective response (BOR) that was lesion specific. Secondary outcomes included overall objective response (OOR), response durability, radiation necrosis (RN), and overall survival (OS).

Results: One hundred fifty patients underwent SRS to 1003 BM and received ICI. Five hundred sixty-four lesions (56%) treated with concurrent ICI (±5 half-lives) demonstrated superior BOR, OOR, and response durability compared with lesions treated with SRS and delayed ICI. Responses were best in those treated with immediate (±1 half-life) ICI (BOR: -100 vs -57%, P < 0.001; complete response: 50 vs 32%; 12-month durable response: 94 vs 71%, P < 0.001). Lesions pre-exposed to ICI and treated with SRS had poorer BOR (-45%) compared with ICI naive lesions (-63%, P < 0.001); best response was observed in ICI naive lesions receiving SRS and immediate ICI (-100%, P < 0.001). The 12-month cumulative incidence of RN with immediate ICI was 3.2% (95% CI: 1.3-5.0%). First radiographic follow-up and best intracranial response were significantly associated with longer OS; steroids were associated with inferior response rates and poorer OS (median 10 vs 25 mo, P = 0.002).

Conclusions: Sequencing of ICI around SRS is associated with overall response, best response, and response durability, with the most substantial effect in ICI naive BM undergoing immediate combined modality therapy. First intracranial response for patients treated with immediate ICI and SRS may be prognostic for OS, whereas steroids are detrimental.
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http://dx.doi.org/10.1093/neuonc/noz046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682202PMC
August 2019

Stereotactic radiosurgery with concurrent lapatinib is associated with improved local control for HER2-positive breast cancer brain metastases.

J Neurosurg 2019 02;132(2):503-511

Departments of1Radiation Oncology and.

Objective: With increasing survival for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer in the trastuzumab era, there is an increased risk of brain metastasis. Therefore, there is interest in optimizing intracranial disease control. Lapatinib is a small-molecule dual HER2/epidermal growth factor receptor inhibitor that has demonstrated intracranial activity against HER2+ breast cancer brain metastases. The objective of this study was to investigate the impact of lapatinib combined with stereotactic radiosurgery (SRS) on local control of brain metastases.

Methods: Patients with HER2+ breast cancer brain metastases who underwent SRS from 1997-2015 were included. The primary outcome was the cumulative incidence of local failure following SRS. Secondary outcomes included the cumulative incidence of radiation necrosis and overall survival.

Results: One hundred twenty-six patients with HER2+ breast cancer who underwent SRS to 479 brain metastases (median 5 lesions per patient) were included. Among these, 75 patients had luminal B subtype (hormone receptor-positive, HER2+) and 51 patients had HER2-enriched histology (hormone receptor-negative, HER2+). Forty-seven patients received lapatinib during the course of their disease, of whom 24 received concurrent lapatinib with SRS. The median radiographic follow-up among all patients was 17.1 months. Concurrent lapatinib was associated with reduction in local failure at 12 months (5.7% vs 15.1%, p < 0.01). For lesions in the ≤ 75th percentile by volume, concurrent lapatinib significantly decreased local failure. However, for lesions in the > 75th percentile (> 1.10 cm3), concurrent lapatinib did not significantly improve local failure. Any use of lapatinib after development of brain metastasis improved median survival compared to SRS without lapatinib (27.3 vs 19.5 months, p = 0.03). The 12-month risk of radiation necrosis was consistently lower in the lapatinib cohort compared to the SRS-alone cohort (1.3% vs 6.3%, p < 0.01), despite extended survival.

Conclusions: For patients with HER2+ breast cancer brain metastases, the use of lapatinib concurrently with SRS improved local control of brain metastases, without an increased rate of radiation necrosis. Concurrent lapatinib best augments the efficacy of SRS for lesions ≤ 1.10 cm3 in volume. In patients who underwent SRS for HER2+ breast cancer brain metastases, the use of lapatinib at any time point in the therapy course was associated with a survival benefit. The use of lapatinib combined with radiosurgery warrants further prospective evaluation.
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http://dx.doi.org/10.3171/2018.10.JNS182340DOI Listing
February 2019

Stereotactic radiosurgery with concurrent HER2-directed therapy is associated with improved objective response for breast cancer brain metastasis.

Neuro Oncol 2019 05;21(5):659-668

Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.

Background: Patients with breast cancer positive for human epidermal growth factor receptor 2 (HER2) remain at high risk of intracranial relapse following treatment and experience increased rates of intracranial failure after stereotactic radiosurgery (SRS). We hypothesized that the addition of concurrent lapatinib to SRS would improve intracranial complete response rates.

Methods: Patients with newly diagnosed HER2-amplified breast cancer brain metastases from 2005-2014 who underwent SRS were included and divided into 2 cohorts based on timing of treatment with lapatinib. Outcome variables included the proportion of patients who achieved an intracranial complete response or progressive disease according to the RECIST 1.1 criteria, as well as individual lesion response rates, distant intracranial failure, and radiation necrosis.

Results: Eighty-four patients with 487 brain metastases met inclusion criteria during the study period. Over 138 treatment sessions, 132 lesions (27%) were treated with SRS and concurrent lapatinib, while 355 (73%) were treated with SRS without lapatinib. Compared with patients treated with SRS alone, patients treated with concurrent lapatinib had higher rates of complete response (35% vs 11%, P = 0.008). On a per-lesion basis, best objective response was superior in the concurrent lapatinib group (median 100% vs 70% reduction, P < 0.001). Concurrent lapatinib was not associated with an increased risk of grade 2+ radiation necrosis (1.0% with concurrent lapatinib vs 3.5% without, P = 0.27). Lapatinib had no protective effect on distant intracranial failure rates (48% vs 49%, P = 0.91).

Conclusion: The addition of concurrent lapatinib to SRS was associated with improved complete response rates among patients with HER2-positive brain metastases.
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http://dx.doi.org/10.1093/neuonc/noz006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502492PMC
May 2019

Overall survival and response to radiation and targeted therapies among patients with renal cell carcinoma brain metastases.

J Neurosurg 2019 Jan 18:1-9. Epub 2019 Jan 18.

Departments of1Radiation Oncology and.

Objective: The object of this retrospective study was to investigate the impact of targeted therapies on overall survival (OS), distant intracranial failure, local failure, and radiation necrosis among patients treated with radiation therapy for renal cell carcinoma (RCC) metastases to the brain.

Methods: All patients diagnosed with RCC brain metastasis (BM) between 1998 and 2015 at a single institution were included in this study. The primary outcome was OS, and secondary outcomes included local failure, distant intracranial failure, and radiation necrosis. The timing of targeted therapies was recorded. Multivariate Cox proportional-hazards regression was used to model OS, while multivariate competing-risks regression was used to model local failure, distant intracranial failure, and radiation necrosis, with death as a competing risk.

Results: Three hundred seventy-six patients presented with 912 RCC BMs. Median OS was 9.7 months. Consistent with the previously validated diagnosis-specific graded prognostic assessment (DS-GPA) for RCC BM, Karnofsky Performance Status (KPS) and number of BMs were the only factors prognostic for OS. One hundred forty-seven patients (39%) received vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Median OS was significantly greater among patients receiving TKIs (16.8 vs 7.3 months, p < 0.001). Following multivariate analysis, KPS, number of metastases, and TKI use remained significantly associated with OS.The crude incidence of local failure was 14.9%, with a 12-month cumulative incidence of 13.4%. TKIs did not significantly decrease the 12-month cumulative incidence of local failure (11.4% vs 14.5%, p = 0.11). Following multivariate analysis, age, number of BMs, and lesion size remained associated with local failure. The 12-month cumulative incidence of radiation necrosis was 8.0%. Use of TKIs within 30 days of SRS was associated with a significantly increased 12-month cumulative incidence of radiation necrosis (10.9% vs 6.4%, p = 0.04).

Conclusions: Use of targeted therapies in patients with RCC BM treated with intracranial SRS was associated with improved OS. However, the use of TKIs within 30 days of SRS increases the rate of radiation necrosis without improving local control or reducing distant intracranial failure. Prospective studies are warranted to determine the optimal timing to reduce the rate of necrosis without detracting from survival.
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http://dx.doi.org/10.3171/2018.8.JNS182100DOI Listing
January 2019

Outcomes and prognostic stratification of patients with recurrent glioblastoma treated with salvage stereotactic radiosurgery.

J Neurosurg 2018 10;131(2):489-499

1The Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland.

Objective: Glioblastoma (GBM) is the most malignant form of astrocytoma. The average survival is 6-10 months in patients with recurrent GBM (rGBM). In this study, the authors evaluated the role of stereotactic radiosurgery (SRS) in patients with rGBMs.

Methods: The authors performed a retrospective review of their brain tumor database (1997-2016). Overall survival (OS) and progression-free survival (PFS) after salvage SRS were the primary endpoints evaluated. Response to SRS was assessed using volumetric MR images.

Results: Fifty-three patients with rGBM underwent salvage SRS targeting 75 lesions. The median tumor diameter and volume were 2.55 cm and 3.80 cm3, respectively. The median prescription dose was 18 Gy (range 12-24 Gy) and the homogeneity index was 1.90 (range 1.11-2.02). The median OS after salvage SRS was estimated to be 11.0 months (95% CI 7.1-12.2) and the median PFS after salvage SRS was 4.4 months (95% CI 3.7-5.0). A Karnofsky Performance Scale score ≥ 80 was independently associated with longer OS, while small tumor volume (< 15 cm3) and less homogeneous treatment plans (homogeneity index > 1.75) were both independently associated with longer OS (p = 0.007 and 0.03) and PFS (p = 0.01 and 0.002, respectively). Based on these factors, 2 prognostic groups were identified for PFS (5.4 vs 3.2 months), while 3 were identified for OS (median OS of 15.2 vs 10.5 vs 5.2 months).

Conclusions: SRS is associated with longer OS and/or PFS in patients with good performance status, small-volume tumor recurrences, and heterogeneous treatment plans. The authors propose a prognostic model to identify a cohort of rGBM patients who may benefit from SRS.
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http://dx.doi.org/10.3171/2018.4.JNS172909DOI Listing
October 2018

Contemporary Management of 1-4 Brain Metastases.

Front Oncol 2018 24;8:385. Epub 2018 Sep 24.

Department of Radiation Oncology, Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, United States.

Brain metastases remain the most common neurologic complication of cancer. With improvement in surveillance and systemic therapy, patients with limited CNS disease are living longer after diagnosis, thus influencing the importance of optimal radiation treatment in order to maximize local control and minimize morbidity. In patients with a limited number of brain metastases, stereotactic radiosurgery is more recently seen as an appropriate sole modality for management with excellent local control. As newer systemic therapies emerge and with the advent of immunotherapies and targeted therapies for metastatic CNS disease, further research is needed in the optimal timing and sequencing of these modalities.
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http://dx.doi.org/10.3389/fonc.2018.00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165904PMC
September 2018

Resection Bed Only.

Int J Radiat Oncol Biol Phys 2018 11;102(3):487-488

Department of Radiation Oncology, Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland, Ohio.

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http://dx.doi.org/10.1016/j.ijrobp.2018.05.031DOI Listing
November 2018

Low-grade Glioma, High Stakes Controversy-When and How to Treat in the Molecular Era?

Int J Radiat Oncol Biol Phys 2018 07;101(3):516-517

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.

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http://dx.doi.org/10.1016/j.ijrobp.2018.02.157DOI Listing
July 2018

Risk Factors for Malignant Transformation of Low-Grade Glioma.

Int J Radiat Oncol Biol Phys 2018 03 21;100(4):965-971. Epub 2017 Dec 21.

Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio; Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.

Purpose: The incidence, risk factors, and outcomes of low-grade glioma patients who undergo malignant transformation (MT) in the era of temozolomide are not well known. This study evaluates these factors in a large group of World Health Organization grade 2 glioma patients treated at a tertiary-care institution.

Methods And Materials: Patient, tumor, and treatment factors were analyzed using an institutional review board-approved low-grade glioma database. Characteristics were compared using χ and Wilcoxon signed rank tests. Time to event was summarized using proportional hazards models. Univariate and multivariate survival analyses were performed.

Results: Of a total of 599 patients, 124 underwent MT; 76 (61.3%) had biopsy-proven MT. The MT incidence was 21%, and the median time to MT was 56.4 months. The 5- and 10-year progression-free survival rates were 30.6% ± 4.2% and 4.8% ± 1.9%, respectively, for MT patients and 60% ± 2.4% and 38% ± 2.7%, respectively, for non-MT patients. The 5- and 10-year overall survival rates were 75% ± 4.0% and 46% ± 5.0%, respectively, for MT patients and 87% ± 1.7% and 78% ± 2.3%, respectively, for non-MT patients. On multivariate analysis, older age (P = .001), male sex (P = .004), multiple tumor locations (P = .004), chemotherapy alone (P = .012), and extent of resection (P = .045) remained significant predictors of MT.

Conclusions: MT affects survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our finding that initial interventions could affect the rate of MT is provocative, but these data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT.
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http://dx.doi.org/10.1016/j.ijrobp.2017.12.258DOI Listing
March 2018

Recursive partitioning analysis is predictive of overall survival for patients undergoing spine stereotactic radiosurgery.

J Neurooncol 2018 Apr 3;137(2):289-293. Epub 2018 Jan 3.

Department of Radiation Oncology, Cleveland Clinic, 9500 Euclid Ave, Desk CA5, Cleveland, OH, 44195, USA.

Spine stereotactic radiosurgery (SRS) offers excellent radiographic and pain control for patients with spine metastases. We created a prognostic index using recursive partitioning analysis (RPA) to allow better patient selection for spine SRS. Patients who underwent single-fraction spine SRS for spine metastases were included. Primary histologies were divided into favorable (breast/prostate), radioresistant (renal cell/sarcoma/melanoma) and other. Cox proportional hazards regression was done to identify factors associated with overall survival (OS). RPA was performed to identify factors to classify patients into distinct risk groups with respect to OS. A total of 444 patients were eligible. Median dose was 16 Gy (range 8-18) in 1 fraction and median follow-up was 11.7 months. At time of analysis, 103 (23.1%) patients were alive. Median OS was 12.9 months. RPA identified three distinct classes. Class 1 was defined as KPS > 70 with controlled systemic disease (n = 142); class 3 was defined as KPS ≤ 70 and age < 54 years or KPS ≤ 70 age ≥ 54 years and presence of visceral metastases (n = 95); all remaining patients comprise class 2 (n = 207). Median overall survival was 26.7 months for class 1, 13.4 months for class 2, and 4.5 months for class 3 (p < 0.01). Our analysis demonstrates that there is considerably variability in survival among patients undergoing spine SRS. We created an objective risk stratification via RPA for spine SRS. Given the safety and efficacy of spine SRS and good survival in class 1 and 2 patients, this RPA can help clinicians identify patients who may benefit from upfront spine SRS.
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http://dx.doi.org/10.1007/s11060-017-2716-1DOI Listing
April 2018

Radiation Therapy for Optic Pathway and Hypothalamic Low-Grade Gliomas in Children.

Int J Radiat Oncol Biol Phys 2017 11 23;99(3):642-651. Epub 2017 Jul 23.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. Electronic address:

Purpose: The long-term survival of pediatric patients with optic pathway or hypothalamic low-grade glioma (LGG) who receive radiation therapy (RT) has not been previously assessed.

Methods And Materials: A retrospective study was performed of all patients with optic-hypothalamic pediatric LGG treated with RT at a single institution. Eligible patients were aged ≤21 years at the time of RT and had localized LGG diagnosed by neuroimaging or histology. The median RT dose was 54 Gy, delivered in 30 fractions. Event-free survival (EFS) was defined as survival without progression or secondary high-grade glioma. Days were counted from the first day of RT.

Results: Eighty-nine patients were included in the study, with a median follow-up period of 12.5 years. Of the patients, 14 had neurofibromatosis type 1 (NF-1). The 10-year EFS rate was 61.9% (95% confidence interval [CI], 31.2%-82.1%) for patients with NF-1 and 67.5% (95% CI, 54.8%-77.3%) for those without NF-1. The 10-year overall survival rate was 92.3% (95% CI, 56.6%-98.9%) for patients with NF-1 and 98.4% (95% CI, 89.1%-99.8%) for those without NF-1. Pre-RT chemotherapy (which was more commonly given to younger patients) was associated with reduced EFS, whereas younger age was associated with reduced overall survival. Possible RT-induced neoplasms developed in 8 patients, including 4 with NF-1. The 10-year cumulative incidence of clinically significant vasculopathy was 7.1% (95% CI, 2.9%-13.9%); vasculopathy did not develop in any child aged >10 years at the commencement of RT.

Conclusions: RT is an effective treatment for optic-hypothalamic LGG. Older children without NF-1 have a low risk of late toxicity. RT can be considered for selected younger patients or individuals with NF-1 as a salvage treatment after progression.
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http://dx.doi.org/10.1016/j.ijrobp.2017.07.023DOI Listing
November 2017

Impact of 2-staged stereotactic radiosurgery for treatment of brain metastases ≥ 2 cm.

J Neurosurg 2018 08 22;129(2):366-382. Epub 2017 Sep 22.

1Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute.

OBJECTIVE Stereotactic radiosurgery (SRS) is the primary modality for treating brain metastases. However, effective radiosurgical control of brain metastases ≥ 2 cm in maximum diameter remains challenging and is associated with suboptimal local control (LC) rates of 37%-62% and an increased risk of treatment-related toxicity. To enhance LC while limiting adverse effects (AEs) of radiation in these patients, a dose-dense treatment regimen using 2-staged SRS (2-SSRS) was used. The objective of this study was to evaluate the efficacy and toxicity of this treatment strategy. METHODS Fifty-four patients (with 63 brain metastases ≥ 2 cm) treated with 2-SSRS were evaluated as part of an institutional review board-approved retrospective review. Volumetric measurements at first-stage stereotactic radiosurgery (first SSRS) and second-stage SRS (second SSRS) treatments and on follow-up imaging studies were determined. In addition to patient demographic data and tumor characteristics, the study evaluated 3 primary outcomes: 1) response at first follow-up MRI, 2) time to local progression (TTP), and 3) overall survival (OS) with 2-SSRS. Response was analyzed using methods for binary data, TTP was analyzed using competing-risks methods to account for patients who died without disease progression, and OS was analyzed using conventional time-to-event methods. When needed, analyses accounted for multiple lesions in the same patient. RESULTS Among 54 patients, 46 (85%) had 1 brain metastasis treated with 2-SSRS, 7 patients (13%) had 2 brain metastases concurrently treated with 2-SSRS, and 1 patient underwent 2-SSRS for 3 concurrent brain metastases ≥ 2 cm. The median age was 63 years (range 23-83 years), 23 patients (43%) had non-small cell lung cancer, and 14 patients (26%) had radioresistant tumors (renal or melanoma). The median doses at first and second SSRS were 15 Gy (range 12-18 Gy) and 15 Gy (range 12-15 Gy), respectively. The median duration between stages was 34 days, and median tumor volumes at the first and second SSRS were 10.5 cm (range 2.4-31.3 cm) and 7.0 cm (range 1.0-29.7 cm). Three-month follow-up imaging results were available for 43 lesions; the median volume was 4.0 cm (range 0.1-23.1 cm). The median change in volume compared with baseline was a decrease of 54.9% (range -98.2% to 66.1%; p < 0.001). Overall, 9 lesions (14.3%) demonstrated local progression, with a median of 5.2 months (range 1.3-7.4 months), and 7 (11.1%) demonstrated AEs (6.4% Grade 1 and 2 toxicity; 4.8% Grade 3). The estimated cumulative incidence of local progression at 6 months was 12% ± 4%, corresponding to an LC rate of 88%. Shorter TTP was associated with greater tumor volume at baseline (p = 0.01) and smaller absolute (p = 0.006) and relative (p = 0.05) decreases in tumor volume from baseline to second SSRS. Estimated OS rates at 6 and 12 months were 65% ± 7% and 49% ± 8%, respectively. CONCLUSIONS 2-SSRS is an effective treatment modality that resulted in significant reduction of brain metastases ≥ 2 cm, with excellent 3-month (95%) and 6-month (88%) LC rates and an overall AE rate of 11%. Prospective studies with larger cohorts and longer follow-up are necessary to assess the durability and toxicities of 2-SSRS.
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http://dx.doi.org/10.3171/2017.3.JNS162532DOI Listing
August 2018

Melanoma brain metastasis: the impact of stereotactic radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on treatment outcome.

J Neurosurg 2018 07 11;129(1):50-59. Epub 2017 Aug 11.

2Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

OBJECTIVE The goal of this study was to investigate the impact of stereotactic radiosurgery (SRS), BRAF status, and targeted and immune-based therapies on the recurrence patterns and factors associated with overall survival (OS) among patients with melanoma brain metastasis (MBM). METHODS A total of 366 patients were treated for 1336 MBMs; a lesion-based analysis was performed on 793 SRS lesions. The BRAF status was available for 78 patients: 35 had BRAF and 43 had BRAF wild-type ( BRAF-WT) lesions. The Kaplan-Meier method evaluated unadjusted OS; cumulative incidence analysis determined the incidences of local failure (LF), distant failure, and radiation necrosis (RN), with death as a competing risk. RESULTS The 12-month OS was 24% (95% CI 20%-29%). On multivariate analysis, younger age, lack of extracranial metastases, better Karnofsky Performance Status score, and fewer MBMs, as well as treatment with BRAF inhibitors (BRAFi), anti-PD-1/CTLA-4 therapy, or cytokine therapy were significantly associated with OS. For patients who underwent SRS, the 12-month LF rate was lower among those with BRAF lesions (6%, 95% CI 2%-11%) compared with those with BRAF-WT lesions (22%, 95% CI 13%-32%; p < 0.01). The 12-month LF rates among lesions treated with BRAFi and PD-1/CTLA-4 agents were 1% (95% CI 1%-4%) and 7% (95% CI 1%-13%), respectively. On multivariate analysis, BRAF inhibition within 30 days of SRS was protective against LF (HR 0.08, 95% CI 0.01-0.55; p = 0.01). The 12-month rates of RN were low among lesions treated with BRAFi (0%, 95% CI 0%-0%), PD-1/CTLA-4 inhibitors (2%, 95% CI 1%-5%), and cytokine therapies (6%, 95% CI 1%-13%). CONCLUSIONS Prognostic schema should incorporate BRAFi or immunotherapy status and use of targeted therapies. Treatment with a BRAF inhibitor within 4 weeks of SRS improves local control without an increased risk of RN.
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http://dx.doi.org/10.3171/2017.1.JNS162797DOI Listing
July 2018

First follow-up radiographic response is one of the predictors of local tumor progression and radiation necrosis after stereotactic radiosurgery for brain metastases.

Cancer Med 2017 Sep 4;6(9):2076-2086. Epub 2017 Aug 4.

Department of Neurosurgery, The Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue, CA-50, Cleveland, Ohio, 44195.

Local progression (LP) and radiation necrosis (RN) occur in >20% of cases following stereotactic radiosurgery (SRS) for brain metastases (BM). Expected outcomes following SRS for BM include tumor control/shrinkage, local progression and radiation necrosis. 1427 patients with 4283 BM lesions were treated using SRS at Cleveland Clinic from 2000 to 2012. Clinical, imaging and radiosurgery data were collected from the database. Local tumor progression and RN were the primary end points and correlated with patient and tumor-related variables. 5.7% of lesions developed radiographic RN and 3.6% showed local progression at 6 months. Absence of new extracranial metastasis (P < 0.001), response to SRS at first follow-up scan (local progression versus stable size (P < 0.001), partial resolution versus complete resolution at first follow up [P = 0.009]), prior SRS to the same lesion (P < 0.001), IDL% (≤55; P < 0.001), maximum tumor diameter (>0.9 cm; P < 0.001) and MD/PD gradient index (≤1.8, P < 0.001) were independent predictors of high risk of local tumor progression. Absence of systemic metastases (P = 0.029), good neurological function at 1st follow-up (P ≤ 0.001), no prior SRS to other lesion (P = 0.024), low conformity index (≤1.9) (P = 0.009), large maximum target diameter (>0.9 cm) (P = 0.003) and response to SRS (tumor progression vs. stable size following SRS [P < 0.001]) were independent predictors of high risk of radiographic RN. Complete tumor response at first follow-up, maximum tumor diameter <0.9 cm, tumor volume <2.4 cc and no prior SRS to the index lesion are good prognostic factors with reduced risk of LP following SRS. Complete tumor response to SRS, poor neurological function at first follow-up, prior SRS to other lesions and high conformity index are favorable factors for not developing RN. Stable or partial response at first follow-up after SRS have same impact on local progression and RN compared to those with complete resolution or progression.
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http://dx.doi.org/10.1002/cam4.1149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603831PMC
September 2017

Pseudoprogression in pediatric low-grade glioma after irradiation.

J Neurooncol 2017 Nov 27;135(2):371-379. Epub 2017 Jul 27.

Department of Radiation Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 210, Memphis, TN, 38105, USA.

This study aimed to assess the incidence and management of pseudoprogression after radiation therapy (RT) in patients with pediatric low-grade glioma (LGG). This retrospective review included patients aged 21 years or younger with intracranial LGG treated with curative-intent RT. Pseudoprogression was defined as an increase in tumor size by ≥10% in at least two dimensions between two and three consecutive MR imaging studies. Overall survival (OS) and event-free survival (EFS) were measured from the first day of RT. EFS was defined as survival without true progression or secondary high-grade glioma. Sixty-two of 221 patients developed pseudoprogression, with a 10-year cumulative incidence of 29.0% (95% CI 23.0-35.2). Median time to pseudoprogression was 6.1 months after RT. Symptomatic pseudoprogression was managed with subtotal resection, shunt/Ommaya reservoir placement, or corticosteroids in 11 (18%), 7 (11%), and 2 patients (3%), respectively. The remaining tumors were observed (68%). Patients with pilocytic astrocytoma (PA) had 5.4-fold greater odds of developing pseudoprogression relative to tumors of other histology (odds ratio 95% CI 2.5-11.4, P < 0.0001). Among patients with PA (n = 127), the 10-year cumulative incidence of pseudoprogression was 42.9%. In this group, pseudoprogression was associated with improved 10-year EFS (84.5% vs. 58.5%, P = 0.008) and OS (98.0% vs. 91.2%, P = 0.03). Pseudoprogression after irradiation was common, especially in patients with pilocytic astrocytoma, and was associated with improved survival. Knowledge of the incidence and temporal course of pseudoprogression may help avoid unnecessary salvage therapy.
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http://dx.doi.org/10.1007/s11060-017-2583-9DOI Listing
November 2017

Validation of the Disease-Specific GPA for Patients With 1 to 3 Synchronous Brain Metastases in Newly Diagnosed NSCLC.

Clin Lung Cancer 2018 01 6;19(1):e141-e147. Epub 2017 Jul 6.

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.

Background: The disease-specific graded prognostic assessment (DS-GPA) for brain metastases is a powerful prognostic tool but has not been validated for patients with synchronous brain metastases (SBM) in newly diagnosed non-small-cell lung cancer (NSCLC).

Patients And Methods: We identified patients with newly diagnosed NSCLC with 1 to 3 SBM treated with stereotactic radiosurgery (SRS) between 1997 and 2012. We included patients whose brain metastases were treated with SRS alone or combined SRS and whole-brain radiotherapy (WBRT). Patients were stratified according to NSCLC DS-GPA to evaluate the accuracy of survival estimates.

Results: One hundred sixty-four patients were treated with either SRS alone (n = 85; 52%) or SRS and WBRT (n = 79; 48%). Median overall survival (OS) stratified according to DS-GPA of 0 to 1, 1.5 to 2, 2.5 to 3, and 3.5 to 4 were 2.8, 6.7, 9.8, and 13.2 months, respectively, consistent with OS reported for brain metastases in NSCLC DS-GPA (3.0, 6.5, 11.3, and 14.8 months, respectively). No difference in median progression-free survival or OS was noted with combined use of SRS and WBRT: 6.0 versus 6.1 months (P = .81) and 8.5 versus 9.1 months (P = .093), respectively. In multivariable analysis, Karnofsky performance status (hazard ratio [HR], 0.98; P = .008), extracranial metastases (HR, 0.498; P = .0003), squamous histology (HR, 1.81; P = .02), and number of brain metastases (2 vs. 1; HR, 1.504; P = .04, and 3 vs. 1; HR, 1.66; P = .05) were significant predictors of OS.

Conclusion: The DS-GPA accurately estimates the prognosis of patients with SBM in newly diagnosed NSCLC. Patients with synchronous brain metastasis in newly diagnosed NSCLC should be carefully stratified for consideration of aggressive therapy.
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http://dx.doi.org/10.1016/j.cllc.2017.06.011DOI Listing
January 2018

Cumulative Intracranial Tumor Volume and Number of Brain Metastasis as Predictors of Developing New Lesions After Stereotactic Radiosurgery for Brain Metastasis.

World Neurosurg 2017 Oct 19;106:666-675. Epub 2017 Jul 19.

The Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Department of Neurosurgery and Neurooncology, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA. Electronic address:

Objectives: To identify risk factors associated with early distant radiographic progression in patients undergoing stereotactic radiosurgery (SRS) for brain metastases (BM).

Methods: Following Institutional Review Board approval, data of 1427 patients (4283 BM lesions) who were treated by SRS at the Cleveland Clinic for 2000-2012 were collected. Local tumor progression (LTP), distant tumor progression (DTP), and radiographic radiation necrosis (RN) were the primary endpoints. Patient, imaging, radiosurgery, and tumor variables and follow-up data were collected.

Results: The median number of targets was 2 (range, 1-17); 45% of the patients had a single lesion. DTP was observed in 10% at 3 months and 19% at 6 months. Patients with 5-10 target lesions for SRS were more likely to develop new lesions at both 3 and 6 months compared to those with 2-4 lesions (odds ratio [OR], 0.83, 95% confidence interval [CI], 0.40-0.85 and OR, 0.85, 95% CI, 0.45-0.86 respectively; P < 0.05). Younger age (<65 years; P < 0.001), higher number of lesions (>1; P < 0.001), cumulative intracranial tumor volume (CITV) <2.75 cc (P = 0.023), type of SRS (upfront and salvage vs. boost; P < 0.001), and tumor pathology (radiosensitive; P < 0.001), were independent predictors of early distant tumor progression following SRS.

Conclusions: The number of target lesions and low CITV are both independent predictors of early DTP following SRS for BM. Radiosensitive tumor histology, younger age (<65 years), and SRS without previous whole-brain radiation therapy (upfront or salvage) were also predictors of early DTP.
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http://dx.doi.org/10.1016/j.wneu.2017.07.048DOI Listing
October 2017

Stereotactic Radiosurgery for Trigeminal Neuralgia Improves Patient-Reported Quality of Life and Reduces Depression.

Int J Radiat Oncol Biol Phys 2017 08 11;98(5):1078-1086. Epub 2017 Apr 11.

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Purpose: To characterize quality-of-life (QOL) outcomes after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN).

Methods And Materials: The EuroQOL 5 Dimensions (EQ-5D) and Patient Health Questionnaire 9 (PHQ-9) were prospectively collected before and after SRS for 50 patients with TN. Pain response and treatment-related facial numbness were classified by Barrow Neurological Institute (BNI) scales. Differences in pooled QOL outcomes were tested with paired t tests and sign tests. The Kaplan-Meier method was used to estimate time-dependent improvements in the EQ-5D index, EQ-5D perceived health status (PHS), PHQ-9 score, and freedom from pain failure (BNI class IV-V) or facial numbness (BNI class III-IV).

Results: Following SRS, the 12-month rate of freedom from pain failure was 92% (95% confidence interval [CI], 77%-97%) while the 12-month rate of freedom from facial numbness was 89% (95% CI, 66%-97%). Significant improvements in the EQ-5D index (P<.01), PHS (P=.01), and PHQ-9 (P=.03) were observed, driven by the EQ-5D subscores for self-care and for pain and/or discomfort (P=.02 and P<.01, respectively). At 12 months after SRS, the actuarial rates of improvement in the EQ-5D, PHS, and PHQ-9 were 55% (95% CI, 40%-70%), 59% (95% CI, 40%-76%), and 59% (95% CI, 39%-76%), respectively. The median time to improvement in each of the QOL measures was 9 months (95% CI, 3-36 months) for the EQ-5D index, 5 months (95% CI, 3-36 months) for PHS, and 9 months (95% CI, 3-18 months) for the PHQ-9. On multivariate analysis, only higher prescription dose (86 Gy vs ≤82 Gy) was associated with improvement in the EQ-5D index (hazard ratio, 5.73; 95% CI, 1.85-22.33; P<.01).

Conclusions: Patients with TN treated with SRS reported significant improvements in multiple QOL measures, with the therapeutic benefit strongly driven by improvements in pain and/or discomfort and in self-care, along with lower rates of depression. In this analysis, there appears to be a correlation between prescription dose and treatment response as measured by the EQ-5D.
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http://dx.doi.org/10.1016/j.ijrobp.2017.04.008DOI Listing
August 2017

Intensity modulated radiation therapy with pulsed reduced dose rate as a reirradiation strategy for recurrent central nervous system tumors: An institutional series and literature review.

Pract Radiat Oncol 2017 Nov - Dec;7(6):e391-e399. Epub 2017 Apr 12.

Department of Radiation Oncology, Cleveland Clinic Radiation Oncology, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-oncology Center, Cleveland, Ohio.

Background: Pulsed reduced dose rate (PRDR) is a reirradiation technique that potentially overcomes volume and dose limitations in the setting of previous radiation therapy for recurrent central nervous system (CNS) tumors. Intensity modulated radiation therapy (IMRT) has not yet been reported as a PRDR delivery technique. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for CNS reirradiation.

Methods And Materials: A total of 24 patients with recurrent brain tumors received PRDR reirradiation between August 2012 and December 2014. Twenty-two patients were planned with IMRT. Linear accelerators delivered an effective dose rate of 0.0667 Gy/minute. Data collected included number of prior interventions, diagnosis, tumor grade, radiation therapy dose and fractionation, normal tissue dose, radiation therapy planning parameters, time to progression, overall survival, and adverse events.

Results: The median time to PRDR from completion of initial radiation therapy was 47.8 months (range, 11-389.1 months). The median PRDR dose was 54 Gy (range, 38-60 Gy). The mean planning target volume was 369.1 ± 177.9 cm. The median progression-free survival and 6-month progression-free survival after PRDR treatment was 3.1 months and 31%, respectively. The median overall survival and 6-month overall survival after PRDR treatment was 8.7 months and 71%, respectively. Fifty percent of patients had ≥4 chemotherapy regimens before PRDR. Toxicity was similar to initial treatment, including no cases of radiation necrosis.

Conclusion: IMRT PRDR reirradiation is a feasible and appropriate treatment strategy for large volume recurrent CNS tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated. Prospective studies are necessary to determine the optimal timing of PRDR reirradiation, the role of concurrent systemic agents, and the ideal patient population who would receive the maximal benefit from this treatment approach.

Summary: Intensity modulated radiation therapy (IMRT) has not yet been reported as a pulsed reduced dose rate (PRDR) delivery technique for recurrent brain tumors and may allow for safe and comprehensive reirradiation for large volume tumors. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for recurrent central nervous system tumors. We conclude that IMRT PRDR reirradiation is a feasible and appropriate treatment strategy for large volume recurrent brain tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated.
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http://dx.doi.org/10.1016/j.prro.2017.04.003DOI Listing
July 2018

Craniospinal irradiation for treatment of metastatic pediatric low-grade glioma.

J Neurooncol 2017 Sep 17;134(2):317-324. Epub 2017 Jun 17.

Department of Radiation Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 210, Memphis, TN, 38105, USA.

Patients with disseminated pediatric low-grade glioma (LGG) initially treated with chemotherapy frequently experience disease progression, with 5-year event-free survival (EFS) of <20% and 10-year overall survival (OS) of approximately 70%. This study aimed to describe outcomes of metastatic pediatric LGG treated with craniospinal irradiation (CSI). A retrospective study was performed of all patients with metastatic pediatric LGG treated with CSI at a single institution. EFS was defined as survival without disease progression or secondary high-grade glioma. Dates were counted from the first day of irradiation. We identified 12 eligible patients; all had histologically confirmed LGG. Metastatic disease was present at initial presentation in 9 patients. The median age at CSI was 9.3 years. The 5-year EFS and OS were 71% (95% CI 33.7-89.5) and 70% (95% CI 32.9-89.2), respectively. No deaths were observed among the patients who underwent subtotal resection (STR) before radiotherapy, whereas 3 patients who had undergone biopsy died (OS log-rank P = 0.01). EFS may be longer among patients who underwent STR before RT (EFS log-rank P = 0.03), with a hazard ratio for biopsy of 8.4 (vs. STR; 95% CI 0.8-84.0, P = 0.07). No patient experienced acute toxicity of grade 3 or higher. Patients with metastatic pediatric LGG treated with CSI experienced longer EFS than historical cohorts treated with chemotherapy alone, with similar OS. CSI may be considered in the management of metastatic pediatric LGG, particularly in older children experiencing progression after chemotherapy.
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http://dx.doi.org/10.1007/s11060-017-2525-6DOI Listing
September 2017

The Prognostic Role of Tumor Volume in the Outcome of Patients with Single Brain Metastasis After Stereotactic Radiosurgery.

World Neurosurg 2017 Aug 3;104:229-238. Epub 2017 May 3.

Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA; The Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA. Electronic address:

Background: Patients with single brain metastasis (SBM) have better outcomes after stereotactic radiosurgery (SRS). We analyzed our SRS database to evaluate possible prognostic factors in patients with SBM.

Methods: A total of 584 patients with SBM were treated with SRS at our institution (2000-2012). Study end points were overall survival (OS), and distant and local intracranial progression-free survival (DPFS and LPFS, respectively). Multivariable analysis was performed to develop prognostic models.

Results: Median OS was 10.8 months. A total of 196 patients (36.7%) had distant progression and 102 patients (19.2%) had local progression. New SBM prognostic indices (SPIs) were devised for OS, DPFS, and LPFS. Graded prognostic assessment, neurologic symptoms (P = 0.01), and tumor volume (P = 0.02) were independently associated with OS. The SPI for OS was defined: unfavorable (OS, 7.3 months), intermediate (OS, 10.6 months), and favorable (OS, 19.8 months). For DPFS, age (P = 0.0029), tumor volume (P = 0.0002), and previous whole-brain radiotherapy (P = 0.027) were prognostic and were used to define SPI for DPFS: favorable (6-month cumulative incidence failure [CIF], 10.9%), intermediate (6-month CIF, 16.7%), and unfavorable (6-month CIF, 26.0%) (P < 0.001). For LPFS, graded prognostic assessment (P = 0.0012) and tumor volume (P = 0.0004) were significant, and defined 2 groups in the LPFS SPI: unfavorable (6-month CIF, 12.3%) and favorable (6-month CIF, 6%) (P < 0.001).

Conclusions: This is the largest series of patients with SBM treated with SRS analyzed for OS, LPFS, and DPFS. SPI was devised for end points. Tumor volume had a significant association with all 3 end points. Neurologic symptoms, age, and previous whole-brain radiotherapy were also found to be prognostic.
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http://dx.doi.org/10.1016/j.wneu.2017.04.156DOI Listing
August 2017